4dxx

TGT K52M mutant crystallized at pH 8.5

spinqualitylabelsall models 4dxx, resolution 1.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4dxx is a 1 chain structure with sequence from Zymomonas mobilis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DMS, GOL, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TGT_ZYMMO] Exchanges the guanine residue with 7-aminomethyl-7-deazaguanine in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr). After this exchange, a cyclopentendiol moiety is attached to the 7-aminomethyl group of 7-deazaguanine, resulting in the hypermodified nucleoside queuosine (Q) (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine).[HAMAP-Rule:MF_00168] Publication Abstract from PubMed Interference with protein-protein interactions of interfaces larger than 1500 A2 by small drug-like molecules is notoriously difficult, particularly if targeting homodimers. The tRNA modifying enzyme Tgt is only functionally active as a homodimer. Thus, blocking Tgt dimerization is a promising strategy for drug therapy as this protein is key to the development of Shigellosis. Our goal was to identify hot-spot residues which, upon mutation, results in a predominantly monomeric state of Tgt. The detailed understanding of the spatial location and stability contribution of the individual interaction hot-spot residues and the plasticity of motifs involved in the interface formation is a crucial prerequisite for the rational identification of drug-like inhibitors addressing the respective dimerization interface. Using computational analyses, we identified hot-spot residues that contribute particularly to dimer stability: a cluster of hydrophobic and aromatic residues as well as several salt bridges. This in silico prediction led to the identification of a promising double mutant, which was validated experimentally. Native nano-ESI mass spectrometry showed that the dimerization of the suggested mutant is largely prevented resulting in a predominantly monomeric state. Crystal structure analysis and enzyme kinetics of the mutant variant further support the evidence for enhanced monomerization and provide first insights into the structural consequences of the dimer destabilization. (c) Proteins 2014;. (c) 2014 Wiley Periodicals, Inc. Hot spot analysis to dissect the functional protein-protein interface of a tRNA-modifying enzyme.,Jakobi S, Nguyen TX, Debaene F, Metz A, Sanglier-Cianferani S, Reuter K, Klebe G Proteins. 2014 Jun 28. doi: 10.1002/prot.24637. PMID:24975703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also TRNA-guanine transglycosylase 3D structures

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